PROJECT 3: PROJECT SUMMARY Despite remarkable recent progress, prognosis for patients with advanced melanoma remains poor. Specifically, primary and acquired drug resistance often develops for targeted therapy, and only a subset of patients respond to immunotherapy. These challenges highlight an urgent need to develop novel therapeutic methods, improve current treatments against melanoma, and develop biomarkers that predict response. Emerging evidence suggests that the epigenetic regulator KDM5B is an attractive target and biomarker for melanoma treatment. The long-term goal is to translate our findings of novel mechanisms involved in melanoma formation and progression to the clinic. The objective of this project is to evaluate the therapeutic potential of targeting the KDM5 histone demethylases in melanoma and to develop biomarkers to predict response to PD-1 pathway blockade and combined KDM5 inhibition/immunotherapy. Our central hypothesis is that KDM5 targeting results in direct anti-tumor effects and indirect effects by converting immunologically ?cold? tumors into ?hot? tumors, which are more likely to be infiltrated by lymphocytes and to respond to immune checkpoint blockade. Preliminary data suggests that this effect may be mediated by the STING pathway. The hypothesis is supported by previous studies as well as our own preliminary data from patient-derived melanomas and preclinical melanoma models. The rationale is that better understanding of KDM5 histone demethylase function in melanoma growth and anti-tumor immune responses will result in new and innovative approaches to treat melanoma. The hypotheses will be tested in two Specific Aims: 1) Evaluate the therapeutic potential of targeting KDM5 in melanoma; 2) Evaluate KDM5B as a biomarker in human melanoma. The proposed research is conceptually and translationally innovative, because it aims to determine whether KDM5 inhibition can convert melanomas from an immunologically ?cold? to ?hot? state, and to evaluate tumor KDM5B level as a new biomarker for melanoma. The results from these studies could impact the treatment of patients with melanoma and increase our understanding of the factors that regulate anti-tumor immune responses.